For the treatment of patients with diabetes mellitus who require insulin for the maintenance of glucose homeostasis.

Posology

The dosage should be determined by the physician, according to the requirement of the patient. During changes to a patient’s insulin regimen, increase the frequency of glucose monitoring.

Paediatric population

No data are available

Method of administration

Humulin N should be given by subcutaneous injection but may, although not recommended, also be given by intramuscular injection. This formulation should not be administered intravenously.

Subcutaneous administration should be in the upper arms, thighs, buttocks or abdomen. Use of injection sites should be rotated so that the same site is not used more than approximately once a month in order to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis.

Care should be taken when injecting any Humulin insulin preparations to ensure that a blood vessel has not been entered. After any insulin injection, the injection site should not be massaged. Patients must be educated to use proper injection techniques.

Humulin N (Isophane) may be administered in combination with Humulin R (Soluble). (See Instructions for use and handling for Mixing of Insulins).

Each pack contains a patient information leaflet with instructions on how to inject insulin.

Administer in the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis. During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring.

Transferring a patient to another type or brand of insulin should be done under strict medical supervision. Changes in strength, brand (manufacturer), type (soluble, isophane, mixture), species (animal, human, human insulin analogue), and/or method of manufacture (recombinant DNA versus animal-source insulin) may result in the need for a change in dosage.

Some patients taking human insulin may require a change in dosage from that used with animal-source insulins. If an adjustment is needed, it may occur with the first dose or during the first several weeks or months.

A few patients who experienced hypoglycaemic reactions after transfer to human insulin have reported that the early warning symptoms were less pronounced or different from those experienced with their previous animal insulin. Patients whose blood glucose is greatly improved, e.g. by intensified insulin therapy, may lose some or all of the warning symptoms of hypoglycaemia and should be advised accordingly. Other conditions which may make the early warning symptoms of hypoglycaemia different or less pronounced include long duration of diabetes, diabetic nerve disease, or medications such as beta blockers. Uncorrected hypoglycaemic and hyperglycaemic reactions can cause loss of consciousness, coma or death.

The use of dosages which are inadequate or discontinuation of treatment, especially in insulin-dependent diabetics, may lead to hyperglycaemia and diabetic ketoacidosis; conditions which are potentially lethal.

Treatment with human insulin may cause formation of antibodies, but titres of antibodies are lower than those to purified animal insulin.

Insulin requirements may change significantly in diseases of the adrenal, pituitary or thyroid glands and in the presence of renal or hepatic impairment.

Insulin requirements may be increased during illness or emotional disturbances.

Adjustment of insulin dosage may also be necessary if patients change their level of physical activity or change their usual diet.

Combination of human insulin with pioglitazone

Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. This should be kept in mind, if treatment with the combination of pioglitazone and human insulin is considered. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued, if any deterioration in cardiac symptoms occurs.

Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen

Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia.

Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant antidiabetic products may be needed.

Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycemic control following insulin injections at sites with these reactions. A sudden change in the injection site to an unaffected area has been reported to result in hypoglycemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.

A number of medicinal products are known to interact with glucose metabolism and therefore the physician should be consulted when using other medications in addition to human insulin (see section 4.4). The physician must therefore take possible interactions into account and should always ask his patients about any medicinal products they take.

Insulin requirements may be increased by substances with hyperglycaemic activity, such as glucocorticoids, thyroid hormones, growth hormone, danazol, beta2- sympatomimetics (such as ritodrine, salbutamol, terbutaline), thiazides.

Insulin requirements may be reduced in the presence of substances with hypoglycaemic activity, such as oral hypoglycaemics (OHA), salicylates (for example, acetylsalicylic acid), certain antidepressants (monoamine oxidase inhibitors), certain angiotensin converting enzyme (ACE) inhibitors (captopril, enalapril), angiotensin II receptor blockers, non-selective beta-blocking agents and alcohol.

Somatostatin analogues (octreotide, lanreotide) may both decrease or increase insulin dose requirements.

Pregnancy

Risk Summary

Available data from published studies over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were not performed.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7% and has been reported to be as high as 20-25% in women with a HbA1c >10%. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.

Data

Human Data

While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal  outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.

It is essential to maintain good control of the insulin treated (insulin-dependent or gestational diabetes) patient throughout pregnancy. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Patients with diabetes should be advised to inform their doctors if they are pregnant or are contemplating pregnancy. Careful monitoring of glucose control, as well as general health, is essential in pregnant patients with diabetes.

Lactation

Risk Summary

Available data from published literature suggests that exogenous human insulin products, including HUMULIN N, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including HUMULIN N on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for HUMULIN N and any potential adverse effects on the breastfed child from HUMULIN N or from the underlying maternal condition

Patients with diabetes who are lactating may require adjustments in insulin dose and/or diet.

The patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

Patients should be advised to take precautions to avoid hypoglycaemia whilst driving, this is particularly important in those who have reduced or absent awareness of the warning signs of hypoglycaemia or have frequent episodes of hypoglycaemia. The advisability of driving should be considered in these circumstances.

Hypoglycaemia is the most frequent undesirable effect of insulin therapy that a patient with diabetes may suffer. Severe hypoglycaemia may lead to loss of consciousness, and in extreme cases, death. No specific frequency for hypoglycaemia is presented, since hypoglycaemia is a result of both the insulin dose and other factors e.g. a patient`s level of diet and exercise.

Local allergy in patients is common (≥1/100 to < 1/10). Redness, swelling, and itching can occur at the site of insulin injection. This condition usually resolves in a few days to a few weeks. In some instances, local reactions may be related to factors other than insulin, such as irritants in the skin cleansing agent or poor injection technique.

Systemic allergy, which is very rare (< 1/10,000) but potentially more serious, is a generalised allergy to insulin. It may cause rash over the whole body, shortness of breath, wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases of generalised allergy may be life-threatening. In the rare event of a severe allergy to Humulin, treatment is required immediately. A change of insulin or desensitisation may be required.

Lipodystrophy at the injection site is uncommon (≥1/1,000 to < 1/100).

Cases of oedema have been reported with insulin therapy, particularly if previous poor metabolic control is improved by intensified insulin therapy.

Cutaneous amyloidosis: Frequency ‘not known’.

Lipodystrophy and localized Cutaneous Amyloidosis

Lipodystrophy and localized cutaneous amyloidosis at the injection site have occurred. Hyperglycemia has been reported with repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions (See section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important.  It allows continued monitoring of the benefit/risk balance of the medicinal product.  Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed below.

To report any side effect(s):

- The National Pharmacovigilance Center (NPC):

o Fax: +966-11-205-7662

o SFDA Call Center: 19999 

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

Insulin has no specific overdose definitions, because serum glucose concentrations are a result of complex interactions between insulin levels, glucose availability and other metabolic processes. Hypoglycaemia may occur as a result of an excess of insulin relative to food intake and energy expenditure.
Hypoglycaemia may be associated with listlessness, confusion, palpitations, headache, sweating and vomiting.
Mild hypoglycaemic episodes will respond to oral administration of glucose or sugar products.
Correction of moderately severe hypoglycaemia can be accomplished by intramuscular or subcutaneous administration of glucagon, followed by oral carbohydrate when the patient recovers sufficiently. Patients who fail to respond to glucagon must be given glucose solution intravenously.

If the patient is comatose, glucagon should be administered intramuscularly or subcutaneously. However, glucose solution must be given intravenously, if glucagon is not available or if the patient fails to respond to glucagon. The patient should be given a meal as soon as consciousness is recovered.
Sustained carbohydrate intake and observation may be necessary because hypoglycaemia may occur after apparent clinical recovery.

Pharmacotherapeutic group: Insulins and analogues for injection, intermediate-acting,
ATC code: A10A C01.
Humulin N is an intermediate acting insulin preparation.
The prime activity of insulin is the regulation of glucose metabolism.
In addition insulin has several anabolic and anti-catabolic actions on a variety of different tissues. Within muscle tissue this includes increasing glycogen, fatty acid, glycerol and protein synthesis and amino acid uptake, while decreasing glycogenolysis, gluconeogenesis, ketogenesis, lipolysis, protein catabolism and amino acid output.

The typical activity profile (glucose utilisation curve) following subcutaneous injection is illustrated below by the heavy line. Variations that a patient may experience in timing and/or intensity of insulin activity are illustrated by the shaded area. Individual variability will depend on factors such as size of dose, site of injection temperature and physical activity of the patient.

The pharmacokinetics of insulin do not reflect the metabolic action of that hormone.Therefore, it is more appropriate to examine glucose utilisation curves (as discussed above) when considering the activity of insulin.

Humulin is human insulin produced by recombinant technology. No serious events have been reported in subchronic toxicology studies. Human insulin was not mutagenic in a series of in vitro and in vivo genetic toxicity assays.

m-cresol
glycerol
phenol
protamine sulfate
dibasic sodium phosphate 7H2O
zinc oxide
water for injections.
The following may be used to adjust pH; hydrochloric acid and/or sodium hydroxide.

Humulin preparations should not be mixed with insulins produced by other manufacturers or with animal insulin preparations.

Do not freeze. Do not expose to excessive heat or direct sunlight.

Unopened vials
Store in a refrigerator (2°C - 8°C).

After first use
Store below 30°C.

10 ml of suspension in a vial (type I glass) with a stopper (rubber) sealed with a seal (aluminium) combined with a flip top (plastic). Pack size 1 or 2 or 5 x 1. Not all pack sizes may be marketed.

Do not reuse needles. Dispose of the needle in a responsible manner. Needles must not be shared. Vials can be used until empty, then properly discard. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Dispense in the original sealed carton with the enclosed Instructions for Use.

Instructions for use and handling

A suspension for injection in a 10ml vial to be used in conjunction with an appropriate syringe (100 IU/ml markings).

a) Preparing a dose
Vials containing Humulin N formulation should be rotated several times in the palms of the hands before use to completely resuspend the insulin, until it appears uniformly cloudy or milky. If not, repeat the above procedure until contents are mixed.
Do not shake vigorously as this may cause frothing, which may interfere with the correct measurement of the dose.
The vials should be examined frequently and should not be used if clumps of material are present or if solid white particles stick to the bottom or wall of the vial, giving a frosted appearance.

Mixing of insulins: The shorter acting insulin should be drawn into the syringe first, to prevent contamination of the vial by the longer acting preparation. It is advisable to inject directly after mixing. However, if a delay is necessary, a consistent routine must be followed.

Alternatively a separate syringe or, separate cartridges of Humulin R and N, can be used for administration of the correct amount of each formulation.

Prepare your syringe prior to injection, as directed by your doctor or diabetes specialist nurse.

Use an insulin syringe marked for the strength of insulin being administered.

b) Injecting a dose
Inject the correct dose of insulin, as directed by your doctor or diabetes specialist nurse.

Use of the injection sites should be rotated so that the same is not used more than approximately once a month.

Each pack contains a patient information leaflet with instructions on how to inject insulin.